PROJECT SUMMARY/ABSTRACT Hematopoietic cell transplantation from unrelated donors, haploidentical related donors and cord blood units can cure life-threatening blood disorders; however, graft-versus-host disease (GVHD), relapse and survivorship disparities across different ancestries remain the major obstacles. When matched donors are not available, the properties of HLA mismatches that govern (non)-permissivity are not well-defined. Furthermore, the role of KIR/HLA interactions in modulating relapse remain to be clarified. These deficiencies have important implications for a large fraction of patients who lack HLA-matched donors, and for all patients at risk for disease relapse. We have demonstrated that HLA class I leader peptides, HLA-DP expression, and HLA/KIR interactions each contribute to GVHD, relapse and mortality. The unmet needs are to understand the mechanisms through which HLA and KIR genes modulate transplant risks, and a means to apply the research findings to clinical care. We propose to define the underlying mechanisms through which HLA and KIR genes and proteins function in transplantation, and develop tools for using HLA and KIR in the selection of the optimal transplant donor and cord blood unit. The specific aims are to: define the role of HLA-DP expression and peptide-binding groove pocket in GVHD; define NKG2/HLA-E interactions and HLA-G in GVHD and relapse; define the role for KIR and HLA interaction in relapse after HCT for acute leukemia, and design tools to evaluate gene features in clinical practice. The goals will be achieved through systemic analysis of individual gene variation, haplotypes of genes, and receptor/ligand recognition in large ethnically diverse transplant populations with complete clinical data. This proposal will fill the knowledge gap in the immunobiological basis of GVHD, relapse and survivorship disparities in transplantation. The information will increase the safety, efficacy and availability of transplantation for all patients in need of this life-saving therapy.